EP2315601B1 - Kombination aus einem c-met-antagonisten und einer aminoheteroaryl-verbindung zur behandlung von krebs - Google Patents

Kombination aus einem c-met-antagonisten und einer aminoheteroaryl-verbindung zur behandlung von krebs Download PDF

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EP2315601B1
EP2315601B1 EP09780344.9A EP09780344A EP2315601B1 EP 2315601 B1 EP2315601 B1 EP 2315601B1 EP 09780344 A EP09780344 A EP 09780344A EP 2315601 B1 EP2315601 B1 EP 2315601B1
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cdr
antibody
met
fragment
amino acid
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EP2315601A1 (de
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Liliane Goetsch
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Pierre Fabre Medicament SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the invention relates to a composition comprising a particular antibody antagonist to c-Met and a particular aminoheteroaryl compound, particularly as a medicament.
  • the present invention also comprises a pharmaceutical composition comprising said anti c-Met antibody and said aminoheteroaryl compound as combination products for simultaneous, separate or sequential use.
  • the invention relates to the use of the composition of the invention for the treatment of cancer in a mammal.
  • c-Met is the prototypic member of a sub-family of RTKs which also includes RON and SEA.
  • the c-Met RTK family is structurally different from other RTK families and is the only known high-affinity receptor for hepatocyte growth factor (HGF), also called scatter factor (SF) [ D.P. Bottaro et al., Science 1991, 251: 802-804 ; L. Naldini et al., Eur. Mol. Biol. Org. J. 1991, 10:2867-2878 ].
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c-Met and HGF are widely expressed in a variety of tissue and their expression is normally restricted to cells of epithelial and mesenchymal origin respectively [ M.F.
  • c-Met activation could result from various mechanisms including i) ligand binding, ii) receptor overexpression which leads to spontaneous ligand independent dimerization, or iii) mutations, mainly occurring in the intracellular domain of c-Met, and resulting in increased and persistent phosphorylation of c-Met or in constitutive receptor activation [ J. G. Christensen, Burrows J. and Salgia R., Cancer Letters. 2005, 226:1-26 ].
  • Activated c-Met recruits signaling effectors to its multidocking site located in the cytoplasm domain, resulting in the activation of several key signalling pathways, including Ras-MAPK, PI3K, Src and Stat3 [ Gao CF, Vande Woude GF, Cell Res. 2005, 15(1):49-51 ; Furge KA, Zhang YW, Vande Woude GF, Oncogene. 2000, 19(49):5582-9 ].
  • a unique facet of the c-Met signaling relative to other RTK is its reported interaction with focal adhesion complexes and non-kinase binding partners such as ⁇ 6 ⁇ 4 integrins [ Trusolino L, Bertotti A, Comoglio PM, Cell. 2001, 107:643-54 ], CD44v6 [ Van der Voort R, Taher TE, Wielenga VJ, Spaargaren M, Prevo R, Smit L, David G, Hartmann G, Gherardi E, Pals ST, J Biol Chem.
  • Plexin B1 or semaphorins [ Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM, Nat Cell Biol. 2002, 4(9):720-4 ; Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S, Blood. 2005, 105(11):4321-9 ; Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S, Oncogene.
  • M1268T and H1112Y were sensitive mutations that showed decreased cell growth and motility.
  • Other mutations such as L1213V and Y1248 were found to be resistant to and unaffected by SU11274 [ Hahn O. et al. Hematol Oncol Clin N Am. 2005, 19:343-67 ].
  • HGF/SF antagonist NK4 to prevent ligand binding to c-Met [ Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T, Cancer Res., 2000, 60:6737-43 ], ii) small ATP binding site inhibitors to c-Met that block kinase activity [ Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB, Cancer Res.
  • the inventor has demonstrated that the antibodies antagonists to c-Met, called 224G11, 227H1, 223C4 and 11E1, or functional fragment thereof, described herein and which have been also described in the patent applications EP 07301231.2 filed on July 12, 2007 and US 61/020,639 filed on January 11, 2008 , have the property to inhibit the c-Met dimerization and are active in vivo.
  • the present disclosure relates to a method of treatment of cancer in a mammal which comprises administering to said mammal a therapeutically effective amount of a combination of active components comprising an antagonist to c-Met and an aminoheteroaryl compound.
  • the present invention is directed to a composition
  • a composition comprising a particular antibody antagonist to c-Met, or a c-Met antagonist fragment thereof, and a particular aminoheteroaryl compound, preferably for its use as a medicament.
  • the present invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least:
  • the combination is preferably mixed with an excipient and/or a pharmaceutically acceptable vehicle.
  • composition according to the invention as a medicament.
  • the combination of the invention may be in the form of a kit of parts.
  • the invention therefore includes a product containing a particular antibody antagonist to c-Met, or one of these c-Met antagonist fragments, and a particular aminoheteroaryl compound, as a combined preparation for simultaneous, separate or sequential delivery for the treatment of cancer in a mammal in need thereof.
  • a product contains a particular antibody antagonist to c-Met, or a c-Met antagonist fragment thereof, and a particular aminoheteroaryl compound as defined above as a combined preparation for simultaneous, separate or sequential use in treating a cancer in a mammal in need thereof.
  • the invention provides a pharmaceutical pack containing a course of an anti-cancer treatment for one individual mammal, wherein the pack contains (a) at least one unit of a particular antibody antagonist to c-Met and (b) at least one unit of a particular aminoheteroaryl compound in unit dosage form.
  • the invention deals with a method of treatment of cancer in a mammal which comprises administering to said mammal a therapeutically effective amount of the combination of active components according to the present invention comprising a particular antibody antagonist to c-Met, or c-Met antagonist fragment thereof, and a particular aminoheteroaryl compound.
  • the invention deals with a composition
  • a composition comprising a particular antibody antagonist to c-Met, or c-Met antagonist fragment thereof, and a particular aminoheteroaryl according to the present invention for the treatment of cancer, preferably in a mammal, more preferably in human.
  • Said anti-cancer treatment comprises administering to said mammal a therapeutically effective amount of the composition of the present invention.
  • said composition further comprises a pharmaceutical acceptable carrier and/or excipient.
  • an aminoheteroaryl compound disclosed herein is capable of inhibiting the c-Met protein kinase
  • antibody refers to any immunoglobulin.
  • immunoglobulin include monoclonal antibodies (e.g., full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies or multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity).
  • such molecule consists in a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (or domain) (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions(FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. effector cells) and the first component (Clq) of the classical complement system.
  • They may also include certain antibody functional fragments, as described in greater detail herein, thereof which exhibit the desired binding specificity and affinity, regardless of the source or immunoglobulin type (i.e., IgG, IgE, IgM, IgA, etc.).
  • antagonist it must be understood a compound which is capable of directly counteracting, reducing or inhibiting the biological activity of c-Met.
  • a “therapeutically effective amount” refers to the minimum concentrations or amounts of a compound or of compounds which are effective to prevent, alleviate, reduce or ameliorate symptoms of disease or prolong the survival of the patient being treated. More particularly, in reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of (or preferably eliminating) the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is slowing to some extent, preferably stopping) tumor growth; and/or, (4) relieving to some extent (or preferably eliminating) one or more symptoms associated with the cancer.
  • said antibody antagonist to c-Met, or c-Met antagonist fragment thereof is selected from the group consisting of:
  • said antibody antagonist to c-Met, or c-Met antagonist fragment thereof is selected from the group consisting of:
  • said antibody antagonist to c-Met, or c-Met antagonist fragment thereof are recombinant, chimeric or humanized antibody, or c-Met antagonist fragment thereof, derived from said 224G11, 227H1, 223C4 or 11E1s antibody (derived is intended to designate the antibodies, or c-Met antagonist fragment thereof, comprising at least the 6 CDRs, or at least the light and heavy chain as defined above for each of these antibodies).
  • the present invention relates to a method or a composition according to the invention, wherein said antibody antagonist to c-Met is selected from 224G11, 227H1, 223C4 and 11E1.
  • hybridomas deposited at the CNCM on 03/14/2007 under the numbers CNCM I-3724 (corresponding to 11E1), I-3731 (corresponding to 224G11), I-3732 (corresponding to 227H1) and on 07/06/2007 under the number I-3786 (corresponding to 223C4).
  • These hybridomas consist in murine hybridoma resulting in the cellular fusion of immunized mouse splenocytes with a myeloma cell line (Sp20 Ag14).
  • CDR regions or CDR(s) it is intended to indicate the hypervariable regions of the heavy and light chains of the immunoglobulins as defined by IMGT.
  • the IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species [ Lefranc M.-P., Immunology Today 18, 509 (1997 ); Lefranc M.-P., The Immunologist, 7, 132-136 (1999 ); Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77 (2003 )].
  • cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine 104 (2nd-CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP).
  • the IMGT unique numbering provides a standardized delimitation of the framework regions (FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps represent unoccupied positions, the CDR-IMGT lengths (shown between brackets and separated by dots, e.g. [8.8.13]) become crucial information.
  • the IMGT unique numbering is used in 2D graphical representations, designated as IMGT Colliers de Perles [ Ruiz, M.
  • CDR or CDRs are used here in order to indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognizes.
  • said antibody antagonist to c-Met is the antibody, or one of these c-Met antagonist fragments, derived from the antibody called 224G11 (comprising at least the 6 CDRs SEQ ID Nos. 1, 2, 3, 10, 11 and 12, or at least the SEQ ID Nos. 18 and 21).
  • aminoheteroaryl compounds are known as c-Met inhibitors and present protein tyrosine kinase inhibitor activity.
  • the applicant of the present application is showing for the first time results illustrating a relevant synergy with the combination of a monoclonal antibody antagonist to c-Met as above described with the aminoheteroaryl compound of Formula Ib described in the published patent application WO 2006/021884 .
  • the invention concerns a method of, or a composition for the treatment of cancer in a mammal which comprises administering to said mammal a therapeutically effective amount of a combination of active components comprising at least an antibody antagonist to c-Met as above described and the aminoheteroaryl compound of Formula Ib described in the published patent application WO 2006/021884 .
  • aminoheteroaryl compound of a composition disclosed herein is an enantiomerically pure compound of formula I wherein:
  • Another aminoheteroaryl compound disclosed herein is an enantiomerically pure compound of formula Ia: wherein:
  • aminoheteroaryl compounds disclosed herein are selected from aminopyridine or aminopyrazine compounds.
  • the said aminoheteroaryl compound disclosed herein is preferably, according to an embodiment of the invention, selected from the group consisting of 5-Bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine; 5-iodo-3-[(R)1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)-ethoxy]-pyridin-2-ylamine; 4- ⁇ 5-Amino-6-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-pyrazin-2-yl ⁇ -benzoic acid; (4- ⁇ 5-Amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-e
  • the aminoheteroaryl compound of the invention is a 3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine.
  • Another name given to this chemical compound is PF-02341066 (also written PF-2341066).
  • the reaction mixture was degassed and charged with nitrogen three times, and then stirred at 80°C oil bath under nitrogen for 12 hours.
  • the reaction was cooled to ambient temperature, diluted with ethyl acetate (100 mL), and filtered through a celite pad which was washed with ethyl acetate.
  • the combined ethyl acetate solution 700 mL was washed with water (5x100 mL), brine (100 mL), and dried over Na 2 SO 4 .
  • the invention thus relates to a composition wherein the aminoheteroaryl compound is the compound of formula Ib:
  • the invention concerns a method wherein said cancer is selected from cancers overexpressing c-Met and/or displaying an auto-phosphorylated c-Met.
  • said cancer is selected from prostate cancer, osteosarcomas, lung cancer, breast cancer, endometrial cancer, glioblastoma or colon cancer.
  • the invention relates to a composition as above mentioned, wherein said antibody antagonist to c-Met is selected from the 224G11, 227H1, 223C4 and 11E1 derived antibodies, or from the c-Met antagonist fragments thereof.
  • the said antibody antagonist to c-Met is derived from the 224G11 antibody.
  • aminoheteroaryl compound is the compound of formula Ib:
  • the invention also relates to the use of a composition as defined in the present application for treating cancer in a mammal.
  • said cancer is selected from cancers overexpressing c-Met and/or displaying an auto-phosphorylated c-Met. More particularly, said cancer is selected from prostate cancer, osteosarcomas, lung cancer, breast cancer, endometrial cancer, glyoblastoma or colon cancer.
  • Example 1 In vivo activity of 224G11 and PF-02341066 as single treatments
  • mice In order to verify that the NCI-H441 in vivo model available in the laboratory is sensible to both the 224G11 antibody and the PF-2341066 compound, immunocompromised mice engrafted subcutaneously with NCI-H441 were used. Briefly, NCI-H441 NSCLC cells from ATCC were cultured in RPMI 1640 medium, 10% FCS, 0.1% L-Glutamine. Cells were split two days before engraftment so that they were in exponential phase of growth. Ten million NCI-H441 cells were injected s.c. to Athymic nude mice. Five days after implantation, tumors were measurable and animals were divided into groups of 6 mice with comparable tumor size. For the antibody treatment, mice were treated i.p.
  • PF-02341066 was administered p.o. (oral gavage), daily for a week and then 5 days a week with a double dose the fifth day. Treatment lasted during the whole experiment. Tumor volume was measured twice a week and calculated by the formula: ⁇ /6 X length X width X height.
  • Example 2 In vivo activity of a combination of 224G11 and PF-02341066
  • NCI-H441 cells from ATCC were routinely cultured in RPMI 1640 medium, 10% FCS, 0.1% L-Glutamine. Cells were split two days before engraftment so that they were in exponential phase of growth. Ten million NCI-H441 cells were engrafted to athymic nude mice. Five days after implantation, tumors were measurable and animals were divided into groups of 6 mice with comparable tumor size. For the antibody treatment, mice were treated i.p. with a loading dose of 2 mg of 224G11 Mab/mouse and then twice a week with 1 mg of antibody/mouse. 50 mg/kg of PF-2341066 was administered p.o.
  • mice oral gavage
  • Tumor volume was measured twice a week and calculated by the formula: ⁇ /6 X length X width X height and animal weights were monitored every day over the period of treatment.
  • mice of the control group were sacrificed on day 53 for ethical reasons.
  • the average tumor volume of single modality treated groups is reduced by 64%, 73% and 93% for 224G11, PF-2341066 and 224G11+PF-2341066 respectively.
  • the combined therapy improved significantly tumor growth compared to single therapy treatments (p ⁇ 0.002 compared to PF-2341066 alone and p ⁇ 0.002 compared to 224G11 alone), 1 out of 6 mice being without tumor in the combined therapy group. No significant differences were observed between the 2 single-modality treatment.

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Claims (10)

  1. Zusammensetzung, umfassend einen Antikörperantagonisten gegen c-Met oder ein c-Met-Antagonistfragment davon und eine Aminoheteroarylverbindung,
    wobei der Antikörperantagonist gegen c-Met oder das c-Met-Antagonistfragment davon ausgewählt ist aus der Gruppe bestehend aus:
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nr. 1, 2 und 3; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 10, 11 und 12;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 4, 5 und 6; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 13, 11 und 14;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 7, 8 und 9; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 15, 16 und 17; und
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 47, 48 und 49; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 50, 51 und 52
    und
    wobei die Aminoheteroarylverbindung die Verbindung der Formel Ib ist:
    Figure imgb0053
  2. Teilesatz, umfassend wenigstens:
    (i) eine pharmazeutische Zusammensetzung, umfassend einen Antikörperantagonisten gegen c-Met oder ein c-Met-Antagonistfragment davon; und
    (ii) eine pharmazeutische Zusammensetzung, umfassend eine Aminoheteroarylverbindung,
    als Kombinationsprodukte zur simultanen, separaten oder sequenziellen Verwendung,
    wobei der Antikörperantagonist gegen c-Met oder das c-Met-Antagonistfragment davon ausgewählt ist aus der Gruppe bestehend aus:
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 1, 2 und 3; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 10, 11 und 12;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 4, 5 und 6; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 13, 11 und 14;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 7, 8 und 9; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 15, 16 und 17; und
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, die CDR-H1, CDR-H2 und CDR-H3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 47, 48 und 49; und eine leichte Kette, die CDR-L1, CDR-L2 und CDR-L3 enthält, jeweils umfassend die Aminosäuresequenzen SEQ ID Nrn. 50, 51 und 52
    und
    wobei die Aminoheteroarylverbindung die Verbindung der Formel Ib ist:
    Figure imgb0054
  3. Zusammensetzung oder Teilesatz nach einem der Ansprüche 1 oder 2, wobei der Antikörperantagonist gegen c-Met oder das c-Met-Antagonistfragment davon ausgewählt ist aus der Gruppe bestehend aus:
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, welche die Aminosäuresequenz SEQ ID Nr. 18 umfasst und eine leichte Kette, welche die Aminosäuresequenz SEQ ID Nr. 21 umfasst;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, welche die Aminosäuresequenz SEQ ID Nr. 19 umfasst und eine leichte Kette, welche die Aminosäuresequenz SEQ ID Nr. 22 umfasst;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, welche die Aminosäuresequenz SEQ ID Nr. 20 umfasst und eine leichte Kette, welche die Aminosäuresequenz SEQ ID Nr. 23 umfasst;
    - einem Antikörper oder einem c-Met-Antagonistfragment davon, wobei der Antikörper oder das Fragment davon eine schwere Kette umfasst, welche die Aminosäuresequenz SEQ ID Nr. 53 umfasst und eine leichte Kette, welche die Aminosäuresequenz SEQ ID Nr. 54 umfasst.
  4. Zusammensetzung oder Teilesatz nach einem der Ansprüche 1 bis 3, wobei der Antikörperantagonist gegen c-Met ausgewählt ist aus der Gruppe bestehend aus den monoklonalen Antikörpern, die durch die Hybridome sekretiert werden, die in der Collection Nationale de Cultures de Microorganismes (CNCM, Institut Pasteur, Rue du Docteur Roux, Paris, Frankreich) am 14. März 2007 unter den Nummern I-3724, I-3731, I-3732 und am 6. Juli 2007 unter der Nummer I-3786 abgelegt sind.
  5. Zusammensetzung oder Teilesatz nach einem der Ansprüche 1 bis 4, wobei der Antikörperantagonist gegen c-Met der monoklonale Antikörper, genannt 224G11, ist, der durch das Hybridom sekretiert wird, der in der CNCM am 14. März 2007 unter der Nummer I-3731 abgelegt ist oder der Antikörper oder das c-Met-Antagonistfragment davon ist, der von dem 224G11 Antikörper abgeleitet ist, wobei der Antikörper oder das c-Met-Antagonistfragment davon Folgendes umfasst:
    - wenigstens die 6 CDRs mit den Sequenzen SEQ ID Nrn. 1, 2, 3, 10, 11 und 12; oder
    - wenigstens die schwere Kette, umfassend die Aminosäuresequenz SEQ ID Nr. 18 und eine leichte Kette, umfassend die Aminosäuresequenz SEQ ID Nr. 21.
  6. Zusammensetzung oder Teilesatz nach einem der Ansprüche 1 bis 5 zur Verwendung als ein Medikament.
  7. Zusammensetzung oder Teilesatz nach einem der Ansprüche 1 bis 6 zur Verwendung bei der Behandlung von Krebs.
  8. Zusammensetzung oder Teilesatz zur Verwendung nach Anspruch 7, dadurch gekennzeichnet, dass der Krebs ausgewählt ist aus Krebserkrankungen, die c-Met überexprimieren und/oder ein automatisch phosphoryliertes c-Met anzeigen.
  9. Zusammensetzung oder Teilesatz zur Verwendung nach Anspruch 8, dadurch gekennzeichnet, dass der Krebs ausgewählt ist aus Prostatakrebs, Osteosarkomen, Lungenkrebs, Brustkrebs, Endometriosekrebs, Glioblastom oder Kolonkrebs.
  10. Zusammensetzung oder Teilesatz zur Verwendung nach einem der Ansprüche 7 bis 9 zur Verwendung bei der Behandlung von Krebs bei Säugern, bevorzugt Menschen.
EP09780344.9A 2008-07-08 2009-07-08 Kombination aus einem c-met-antagonisten und einer aminoheteroaryl-verbindung zur behandlung von krebs Active EP2315601B1 (de)

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EP09780344.9A EP2315601B1 (de) 2008-07-08 2009-07-08 Kombination aus einem c-met-antagonisten und einer aminoheteroaryl-verbindung zur behandlung von krebs
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EP2014681A1 (de) * 2007-07-12 2009-01-14 Pierre Fabre Medicament Neue Antikörper zur Hemmung der C-Met-Dimerisation und Verwendungen davon
EP2143441A1 (de) * 2008-07-08 2010-01-13 Pierre Fabre Medicament Kombination aus einem c-MET-Antagonisten und einer Aminoheteroaryl-Verbindung zur Krebsbehandlung
US8545839B2 (en) * 2008-12-02 2013-10-01 Pierre Fabre Medicament Anti-c-Met antibody
JP2013532627A (ja) * 2010-07-01 2013-08-19 武田薬品工業株式会社 ｃＭＥＴ阻害剤とＨＧＦおよび／またはｃＭＥＴに対する抗体との組み合わせ
US20130004484A1 (en) * 2011-06-30 2013-01-03 Genentech, Inc. Anti-c-met antibody formulations
KR101463098B1 (ko) * 2011-11-28 2014-11-27 한국생명공학연구원 ｃ-Ｍｅｔ에 대한 인간항체에 약물이 접합된 약물 복합체 및 이의 용도
CN103204844A (zh) * 2012-01-17 2013-07-17 上海艾力斯医药科技有限公司 氨基杂芳基化合物及其制备方法与应用
US11564915B2 (en) * 2013-04-04 2023-01-31 Exelixis, Inc. Cabozantinib dosage form and use in the treatment of cancer
KR102306656B1 (ko) * 2013-07-03 2021-09-29 삼성전자주식회사 항 c-Met 항체를 이용하는 암의 병용 치료
CN105745335A (zh) * 2013-08-14 2016-07-06 佳根曼斯菲尔德有限公司 用于对cMET核酸进行多模态分析的组合物及方法
WO2015031614A1 (en) * 2013-08-28 2015-03-05 Abbvie Inc. Soluble cmet assay
WO2015031626A1 (en) * 2013-08-28 2015-03-05 Abbvie Inc. Soluble cmet assay
KR102150616B1 (ko) 2013-09-12 2020-09-03 삼성전자주식회사 c-Met 표적 화합물-생체활성 물질 접합체 및 그 용도
EP3200825A4 (de) 2014-10-03 2018-03-21 Academia Sinica Antikörper gegen pathologische formen von tdp-43 und verwendungen davon
WO2016053610A1 (en) * 2014-10-03 2016-04-07 Academia Sinica Antibodies against pathological forms of tdp-43 and uses thereof
TWI782930B (zh) 2016-11-16 2022-11-11 美商再生元醫藥公司 抗ｍｅｔ抗體，結合ｍｅｔ之雙特異性抗原結合分子及其使用方法
CN114340684A (zh) 2019-09-16 2022-04-12 瑞泽恩制药公司 用于免疫pet成像的放射性标记的met结合蛋白

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US20140186356A1 (en) 2014-07-03
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US8623359B2 (en) 2014-01-07
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US9011865B2 (en) 2015-04-21
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